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Chao-Ying Chen,1,2 Kuan-Ying Lee,3 Xavier CC Fung,4 Ji-Kang Chen,5 Yu-Chen Lai,6 Marc N Potenza,7– 12 Kun-Chia Chang,13,14 Chuan-Yin Fang,6 Amir H Pakpour,15 Chung-Ying Lin16– 20 1School of Physical Therapy and Graduate Institute of Rehabilitation Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan; 2New Taipei City Tucheng Hospital (Chang Gung Medical Foundation), Department of Pediatric Internal Medicine, New Taipei City, Taiwan; 3Department of Child and Adolescent Psychiatry, Jianan Psychiatric Center, Ministry of Health and Welfare, Tainan, Taiwan; 4Department of Rehabilitation Sciences, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hung Hom, Hong Kong; 5Department of Social Work, Chinese University of Hong Kong, New Territories, Hong Kong; 6Division of Colon and Rectal Surgery, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, 621, Taiwan; 7Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA; 8Connecticut Mental Health Center, New Haven, CT, USA; 9Connecticut Council on Problem Gambling, Wethersfield, CT, USA; 10Child Study Center, Yale School of Medicine, New Haven, CT, USA; 11Department of Neuroscience, Yale University, New Haven, CT, USA; 12Wu Tsai Institute, Yale University, New Haven, CT, USA; 13Department of General Psychiatry, Jianan Psychiatric Center, Ministry of Health and Welfare, Tainan, Taiwan; 14Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 15Department of Nursing, School of Health and Welfare, Jönköping University, Jönköping, Sweden; 16Institute of Allied Health Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 17Biostatistics Consulting Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 18Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 19Department of Occupational Therapy, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 20INTI International University, Nilai, Negeri Sembilan, 71800, MalaysiaCorrespondence: Kun-Chia Chang, Department of General Psychiatry, Jianan Psychiatric Center, Ministry of Health and Welfare, Tainan, Taiwan, Tel +886-6-2795019 ext. 1532, Fax +886-6-2797659, Email kunchiachang0517@gmail.com Chuan-Yin Fang, Division of Colon and Rectal Surgery, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, 621, Taiwan, Email 04969@cych.org.twBackground: Problematic use of internet (PUI) may have negative impacts on psychological distress and quality of life (QoL). This situation might be more profound in people with attention-deficit/hyperactivity disorder (ADHD) due to poorer behavioral control and regulatory capacity. However, there is little evidence regarding mediated effects in the associations between PUI, psychological distress, and QoL in people with ADHD.Aims: To investigate mediating effects of psychological distress in the associations of problematic smartphone use (PSPU), problematic use of social media (PUSM), and problematic gaming (PG) with QoL in individuals with ADHD.Methods and Procedures: PUI behaviors of participants with ADHD (n = 99) were assessed using the Smartphone Application-Based Addiction Scale, Bergen Social Media Addiction Scale, and Internet Gaming Disorder-Short Form. Psychological distress was assessed using the Depression, Anxiety, Stress Scale and QoL using the Kid-KINDL.Outcomes and Results: Psychological distress mediated the associations between PUI and different domains of QoL, except for self-esteem QoL. There were also positively direct effects between PG and physical QoL, PUSM and friends’ QoL, and PSPU and physical QoL.Conclusions and Implications: PUI may associate with poor QoL in people with ADHD via psychological distress. Programs on reducing PUI for people with ADHD are needed.Keywords: attention-deficit/hyperactivity disorder, ADHD, impulsive behavior, addictive behavior, internet, psychological distress, quality of life

Che-Hsing Li,1,2,&ast; Jiunn-Liang Ko,1,3,4,&ast; Yu-Ping Hsiao,5,6 Ming-Hung Tsai,7 Yen-Chein Lai,8 I-Lun Hsin,3,4 Yu-Ting Kang,3,4 Gwo-Tarng Sheu,1,3,4 Wea-Lung Lin,6,9 Ming-Fang Wu1,4,6 1Divisions of Medical Oncology and Pulmonary Medicine, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, 402, Taiwan; 2Graduate Program in Immunology & Microbiology, Baylor College of Medicine, Houston, TX, 77030, USA; 3Institute of Medicine, Chung Shan Medical University, Taichung, 402, Taiwan; 4CSMU Lung Cancer Research Center, Chung Shan Medical University, Taichung, 402, Taiwan; 5Division of Dermatology, Chung Shan Medical University Hospital, Taichung, 402, Taiwan; 6School of Medicine, Chung Shan Medical University, Taichung, 402, Taiwan; 7Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung, 40447, Taiwan; 8Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, 402, Taiwan; 9Department of Pathology, Chung Shan Medical University Hospital, Taichung, 402, Taiwan&ast;These authors contributed equally to this workCorrespondence: Ming-Fang WuDivisions of Medical Oncology and Pulmonary Medicine, Department of Internal Medicine, Chung Shan Medical University Hospital, 110, Sec. 1, Jianguo N. Road, Taichung, 40201, TaiwanTel +886-4-24739595#34711Email mfwu0111@gmail.comPurpose: Pemetrexed-based chemotherapy (Pem-C) is the first-line chemotherapy for advanced non-squamous non-small cell lung cancer (NSCLC). However, limited tumor-associated proteins in blood are available to predict pemetrexed response and/or survival.Patients and Methods: Plasma samples from three responders and three nonresponders with stage IIIB–IV NSCLC were collected prior to Pem-C and analyzed using Proteome ProfilerTM Human XL Oncology Array to detect 84 oncology-related proteins. The plasma concentrations of cathepsin S, endoglin (ENG), and matrix metalloproteinases 3 and 9 in 71 patients with advanced NSCLC treated with Pem-C were further measured using enzyme-linked immunosorbent assay based on the remarkable differences in the four proteins between responders and nonresponders in the array results.Results: Pem-C responders had significantly higher ENG levels but not the other three markers than nonresponders (mean ENG level: 27.1 ± 7.4 vs 22.3 ± 6.9, p < 0.01). High ENG concentration was correlated with improved progression-free survival (hazard ratio [HR]: 0.52, 95% confidence interval [CI]: 0.31– 0.86, p < 0.01) and overall survival (HR: 0.55, 95% CI: 0.32– 0.94, p < 0.05) in patients treated with Pem-C, and the ENG level was an independent factor in our cohort (HR: 0.54, 95% CI: 0.33– 0.89, p < 0.05). ENG concentration in Pem-C responders also significantly increased at the time of best response (p < 0.05).Conclusion: Cumulatively, this study reveals that ENG is correlated with Pem-C responsiveness in patients, which indicates the potential use of plasma ENG levels as a non-invasive biomarker for pemetrexed-based treatment in patients with non-squamous NSCLC.Keywords: endoglin, pemetrexed-based therapy, prognostic factor, non-squamous non-small cell lung cancer, biomarker

Cheng-Yu Chang,1,&ast; Chung-Yu Chen,2,3,&ast; Shih-Chieh Chang,4– 6,&ast; Yi-Chun Lai,4,5 Yu-Feng Wei7– 9 1Division of Chest Medicine, Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan; 2Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Yunlin County, Taiwan; 3College of Medicine, National Taiwan University, Taipei, Taiwan; 4Division of Chest Medicine, Department of Internal Medicine, National Yang-Ming Chiao Tung University Hospital, Yi-Lan, Taiwan; 5Faculty of Medicine, College of Medicine, National Yang-Ming Chiao Tung University, Taipei, Taiwan; 6Department of Critical Care Medicine, National Yang-Ming Chiao Tung University Hospital, Yi-Lan, Taiwan; 7School of Medicine for International Students, College of Medicine, I-Shou University, Kaohsiung, Taiwan; 8Department of Internal Medicine, E-Da Cancer Hospital, Kaohsiung, Taiwan; 9Institute of Biotechnology and Chemical Engineering, I-Shou University, Kaohsiung, Taiwan&ast;These authors contributed equally to this workCorrespondence: Yu-Feng WeiDepartment of Internal Medicine, E-Da Cancer Hospital, Kaohsiung, Taiwan, No. 21, Yida Road, Jiao-su Village, Yan-chao District, Kaohsiung, 824, TaiwanTel +886-7-6150011Fax +886-7-6150927Email yufeng528@gmail.comIntroduction: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are standard first-line treatments for advanced EGFR-mutated non-small-cell lung cancer (NSCLC) patients. The efficacy of EGFR-TKIs in older patients including poor Eastern Cooperative Oncology Group (ECOG) performance status (PS) is seldom investigated.Methods: We enrolled patients 65 years or older with EGFR-mutated Stage IIIB–IV NSCLC and evaluated the efficacy and prognosis of first-line EGFR-TKI treatment. Clinical and demographic characteristics were reviewed and analyzed, including age, sex, PS, smoking history, EGFR mutation type, treatment regimen, progression-free survival (PFS), and overall survival (OS).Results: From January 2015 to December 2019, a total of 237 patients were included, 205 of whom were eligible for efficacy and outcome analyses. Among them, 91 (44.4%) were categorized as poor PS (2– 4). Compared with patients categorized as good PS (0– 1), those with poor PS were older (79 versus 75 years), had a higher proportion of brain metastases (41.8% versus 25.4%), more comorbidities (74.7% versus 54.4%), and more likely to be treated with first-generation TKIs (74.7% versus 57.0%). The PFS and OS were 17.1 and 26.7 months respectively in patients with good PS and 12.7 and 18.2 months in those with poor PS (both p < 0.001). In the multivariate analysis, good PS, < 3 metastatic sites, and first-line treatment with afatinib compared with erlotinib and gefitinib were associated with longer PFS. A relatively younger age, good PS, < 3 metastatic sites, and no brain metastasis at diagnosis were associated with better OS.Conclusion: In older patients with EGFR-mutated NSCLC and receive EGFR-TKI treatment, a good PS and < 3 metastatic sites at diagnosis were associated with a longer PFS and OS. In addition, afatinib as first-line treatment was associated with a longer PFS whereas a relatively younger age and no brain metastasis at diagnosis were associated with better OS.Keywords: older adults, epidermal growth factor receptor tyrosine kinase inhibitor, non-small-cell lung cancer, performance status

L Leanne Lai¹, Mooi Heong Tan¹, Yen Chi Lai²¹Department of Sociobehavioral and Administrative Pharmacy, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL, USA; ²Department of Internal Medicine, Golen Hospital, Pintong City, TaiwanBackground: The primary objective of our study was to investigate the prevalence of off-label antidepressant drug use in insomnia. The secondary objective was to compare prescribing patterns between off-label antidepressants vs hypnotics approved by the US Food and Drug Administration for insomnia, with particular emphasis on socioeconomic characteristics of patients and physicians.Methods: We undertook a secondary data analysis using the national longitudinal database from the 2006 National Ambulatory Medical Care Survey. Subjects were identified from outpatient visits in which at least one insomnia drug was prescribed. A series of weighted Chi-squared statistics was used to compare drug use for insomnia across various patient and physician characteristics. Multivariate logistic regression was conducted to identify factors associated with off-label antidepressant drug use.Results: Among 901.95 million outpatient visits that took place in the US in 2006, an estimated 30.43 million visits included at least one drug prescription for insomnia. Off-label antidepressants were prescribed significantly more frequently (45.1%) than nonbenzodiazepine z-hypnotics (43.2%) and benzodiazepines (11.7%). Insomnia prescribing patterns were significantly influenced by physician specialty and physician office settings. Pediatricians (odds ratio [OR]: 65.892; 95% confidence interval [CI]: 5.536–810.564) and neurologists (OR: 4.784; 95% CI: 2.044–11.201) were more likely to prescribe off-label antidepressants than psychiatrists. Self-paying patients were more likely to receive off-label antidepressants as treatment for insomnia than patients with private insurance (OR 2.594; 95% CI: 1.128–5.967).Conclusion: Our findings indicate significant socioeconomic disparities in the use of off-label antidepressants. Future studies might explore interventional and educational strategies to ensure well informed clinical decisions that can withstand pharmaceutical marketing strategies and diagnostic uncertainties regarding the treatment of insomnia.Keywords: insomnia, off-label drug use, antidepressants, National Ambulatory Medical Care Survey

Vibrio vulnificus is a marine bacterium causing serious septicemia and wound infection in humans. It produces an RTX toxin that can lyse a variety of cells and is important for virulence in mice. In this study, we explored the role of RTX in pathogenesis by characterizing an RTX-deficient mutant. This mutant showed an ~2-log reduction in virulence for mice infected by various routes. Survival of the mutant at the infection site and subsequent spread into the bloodstream were impaired. In mice pretreated with cyclophosphamide to deplete the neutrophils, both the virulence and survival at the infection site of this mutant were enhanced. This mutant was further shown to be more readily cleared from the macrophage-rich mouse peritoneal cavity and phagocytosed by murine macrophages. These findings suggest that the RTX of V. vulnificus is required for bacterial survival during infection by protecting the organism from phagocytosis. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To evaluate opioid receptor function as a basis for novel antinociceptive therapy in arthritis. METHODS: We induced human mu-opioid receptor (HuMOR) expression in arthritic joints of mice, using the feline immunodeficiency virus (FIV) vector, which is capable of stably transducing dividing, growth-arrested, and terminally differentiated cells. Male and female Col1-IL-1beta(XAT)-transgenic mice developed on a C57BL/6J background and wild-type littermates were studied. RESULTS: A single injection of FIV(HuMOR) into the temporomandibular joints of Col1-IL-1beta(XAT)-transgenic mice 1 week prior to induction of arthritis prevented the development of orofacial pain and joint dysfunction, and reduced the degree of histopathologic abnormality in the joint. In addition, FIV(HuMOR) prevented the attendant sensitization of trigeminal sensory neurons and activation of astroglia in brainstem trigeminal sensory nuclei. These effects were mediated by the transduction of primary sensory neurons via transport of FIV vectors from peripheral nerve endings to sensory ganglia, as evidenced by HuMOR expression in neuronal cell bodies located in the trigeminal ganglia, as well as in their proximal and distal nerve branches located in the main sensory and subnucleus caudalis of the brainstem and joints, respectively. The presence of MOR ligands predominantly in the descending trigeminal nucleus suggested that the observed antinociception occurred at the subnucleus caudalis. Articular chondrocytes and meniscal tissue were also infected by FIV(HuMOR), which presumably exerted an antiinflammatory effect on cartilage. CONCLUSION: Our results indicate that prophylactic therapy with MOR overexpression in joints can successfully prevent the development of pain, dysfunction, and histopathologic abnormalities in the joints in arthritis. These findings may provide a basis for the future development of spatiotemporally controlled antinociceptive and antiinflammatory therapy for arthritis. [ABSTRACT FROM AUTHOR]

Skeletal muscle is a highly adaptable tissue, finely tuned by various physiological and pathological factors. Whilst the pivotal role of skeletal muscle in overall health is widely acknowledged, unravelling the underlying molecular mechanisms poses ongoing challenges. Protein ubiquitylation, a crucial post-translational modification, is involved in regulating most biological processes. This widespread impact is achieved through a diverse set of enzymes capable of generating structurally and functionally distinct ubiquitin modifications on proteins. The complexity of protein ubiquitylation has presented significant challenges in not only identifying ubiquitylated proteins but also characterising their functional significance. Mass spectrometry enables in-depth analysis of proteins and their post-translational modification status, offering a powerful tool for studying protein ubiquitylation and its biological diversity: an approach termed ubiquitylomics. Ubiquitylomics has been employed to tackle different perspectives of ubiquitylation, including but not limited to global quantification of substrates and ubiquitin linkages, ubiquitin site recognition and crosstalk with other post-translational modifications. As the field of mass spectrometry continues to evolve, the usage of ubiquitylomics has unravelled novel insights into the regulatory mechanisms of protein ubiquitylation governing biology. However, ubiquitylomics research has predominantly been conducted in cellular models, limiting our understanding of ubiquitin signalling events driving skeletal muscle biology. By integrating the intricate landscape of protein ubiquitylation with dynamic shifts in muscle physiology, ubiquitylomics promises to not only deepen our understanding of skeletal muscle biology but also lay the foundation for developing transformative muscle-related therapeutics. This review aims to articulate how ubiquitylomics can be utilised by researchers to address different aspects of ubiquitylation signalling in skeletal muscle. We explore methods used in ubiquitylomics experiments, highlight relevant literature employing ubiquitylomics in the context of skeletal muscle and outline considerations for experimental design., (© 2024 The Author(s). Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Carbapenem-resistant Enterobacter cloacae complex is a significant global healthcare threat, particularly carbapenemase-producing Enterobacter hormaechei (CPEH). From January 2017 to January 2021, twenty-two CPEH isolates from a regional teaching hospital in central Taiwan were identified with the carriage of carbapenemase genes bla KPC-2 , bla IMP-8 , and predominantly bla OXA-48 . Over 80% of these CPEH strains clustered into the high-risk ST78 lineage, carrying a bla OXA-48 IncL plasmid (pOXA48-CREH), nearly identical to the endemic plasmid pOXA48-KP in ST11 Klebsiella pneumoniae . This OXA-48-producing ST78 lineage disseminated clonally from 2018 to 2021 and transferred pOXA48-CREH to ST66 and ST90 E. hormaechei . An IMP-8-producing ST78 strain harbouring a bla IMP-8 -carrying pIncHI2 plasmid appeared in 2018, and by late 2020, a KPC-2-producing ST78 strain was identified after acquiring a novel bla KPC-2 -carrying IncFII plasmid. These findings suggest that the high-risk ST78 lineage of E . hormaechei has emerged as the primary driver behind the transmission of CPEH . ST78 has not only acquired various carbapenemase-gene-carrying plasmids but has also facilitated the transfer of pOXA48-CREH to other lineages. Continuous genomic surveillance and targeted interventions are urgently needed to control the spread of emerging CPEH clones in hospital settings.

Objective: Previous studies have shown that the incidence of peptic ulcer disease (PUD) exhibits seasonal variations. This study aimed to investigate the seasonal variation in PUD incidence in Taiwan, which spans both tropical and subtropical regions, using a nationwide database., Methods: A cross-sectional study was conducted using real-world claims data from Taiwan, which includes a representative sample of 2 million individuals. Patients hospitalised with a primary diagnosis of PUD between 2001 and 2019 were identified using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes for gastric ulcers (GUs), duodenal ulcers (DUs) and unspecified peptic ulcers. Descriptive statistics were used to present the seasonal variations in PUD incidence. Patients' gender, age, PUD type, geographical region and non-steroidal anti-inflammatory drugs (NSAIDs) usage across the four seasons (spring, summer, fall, winter) were compared using Pearson's χ 2 test., Results: Among the 13 022 patients, new-onset PUD cases varied annually, peaking at 771 cases in 2004 and reaching a low of 614 cases in 2018. PUD incidence was higher in males than in females, and more common in elderly individuals aged ≥65 (59.5%). GU had the highest prevalence (56.1%), followed by DU (36.3%) and unspecified ulcers (7.7%). PUD incidence peaked in winter (26.8%), followed by spring (25.1%), fall (24.2%) and summer (23.9%). This seasonal trend was consistent across gender and age groups, with no significant impact on latitude, NSAID usage or PUD type., Conclusion: Across the tropical and subtropical regions of Taiwan, seasonal variation in PUD incidence is observed with the highest rates occurring in winter, regardless of age or sex. However, NSAID usage tends to obscure this trend. The seasonal variation in DU incidence showed no significant differences between north and south Taiwan, suggesting that factors other than temperature may affect DU incidence compared with their effect on GU incidence., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Postpartum depression (PPD) is a major mental health issue affecting 10%-15% of women globally. This meta-analysis synthesized updated evidence on sub-anesthetic ketamine/esketamine's efficacy in preventing PPD., Methods: Randomized controlled trials (RCTs) comparing ketamine/esketamine to a placebo for PPD prevention were searched without language restriction. Primary outcomes were PPD risk at 1- and 4-6-week postpartum. Secondary outcomes included the difference in depression scores and risk of adverse events. Trial sequential analysis (TSA) was conducted to validate the reliability., Results: A meta-analysis of 22 RCTs (n = 3,463) showed that ketamine/esketamine significantly decreased PPD risk at 1- (risk ratio [RR], 0.41; 95% confidence interval [CI], 0.3-0.57) and 4-6-week (RR, 0.47; 95%CI, 0.35-0.63) follow-ups. Consistently, participants receiving ketamine/esketamine had lower depression-related scores at 1- (standardized mean difference [SMD], -0.94; 95%CI, -1.26 to -0.62) and 4-6-week (SMD, -0.89; 95%CI, -1.25 to -0.53) follow-ups. Despite potential publication bias, TSA confirmed the evidence's reliability. Subgroup analysis showed that ketamine/esketamine's preventive effect on 1-week PPD was consistent, regardless of administration timing, type of agents, or total dosage (<0.5 vs. ≥0.5 mg/kg). For the 4-6-week period, PPD risk was favorably reduced only with postoperative administration or the use of esketamine, with the total dosage having no observed influence. Participants on ketamine/esketamine experienced more frequency of hallucinations (RR, 4.77; 95%CI, 1.39-16.44) and dizziness (RR, 1.36; 95%CI, 1.02-1.81)., Conclusion: Our findings advocate for the postoperative administration of low-dose ketamine/esketamine to avert PPD, which needed additional research for confirmation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Hung et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Microsatellite instable (MSI) gastric cancers exhibit reduced lymph node (LN) metastasis and improved survival compared to microsatellite stable (MSS) counterparts. However, to our longstanding observation, clinical N-staging (cN) is frequently overestimated in MSI cases. The clinical implications and underlying mechanisms of this discrepancy warrant further investigation., Materials and Methods: We conducted a comprehensive review of clinicopathological data from a 141 MSI and 1119 MSS gastric cancer patients. Expression of vascular endothelial growth factor-C (VEGF-C) and its receptor VEGFR-3 were assessed using qPCR and immunohistochemistry. High-parameter flow cytometry was employed to analyze subsets of CD8+ T cells within the tumors., Results: Multivariate analysis revealed that MSI status was an independent prognostic factor, alongside the LN ratio and AJCC8 pathology staging. MSI gastric cancers exhibited a reduced LN ratio, particularly at advanced T-staging, compared to MSS counterparts, while maintaining an equivalent LN yield. Overestimation of cN by computed tomography preoperatively was frequent in MSI gastric cancers but was more commonly underestimated in MSS counterparts. VEGF-C and VEGFR-3 expression were lower in MSI tumors. MSI gastric cancers showed an increased total number of CD8+ T cells, albeit with a lower proportion of effector memory cells expressing CD45RA (EMRA) and CD8+ CXCR4+ T cells, compared to MSS counterparts., Conclusion: Frequent overestimation of clinical N-staging in MSI gastric cancers is associated with VEGF-C signaling and CD8+ T-cell dynamics and should be cautiously interpreted, as it might misguide therapeutic options., (© The Author(s) 2024. Published by Oxford University Press.)

Idiopathic multicentric Castleman disease (iMCD) is a type of Castleman disease unrelated to the Kaposi sarcoma-associated herpesvirus/human herpesvirus type 8 (KSHV/HHV8) infection. Presently, iMCD is classified into iMCD-IPL (idiopathic plasmacytic lymphadenopathy), iMCD-TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly), and iMCD-NOS (not otherwise specified). The most common treatment for iMCD is using IL-6 inhibitors; however, some patients resist IL-6 inhibitors, especially for iMCD-TAFRO/NOS. Nevertheless, since serum IL-6 levels are not significantly different between the iMCD-IPL and iMCD-TAFRO/NOS cases, cytokines other than IL-6 may be responsible for the differences in pathogenesis. Herein, we performed a transcriptome analysis of cytokine storm-related genes and examined the differences between iMCD-IPL and iMCD-TAFRO/NOS. The results demonstrated that counts per million of STAT2, IL1R1, IL1RAP, IL33, TAFAIP1, and VEGFA (P < 0.001); STAT3, JAK2, MAPK8, IL17RA, IL18, TAFAIP2, TAFAIP3, PDGFA, VEGFC, CXCL10, CCL4, and CXCL13 (P < 0.01); and STAT1, STAT6, JAK1, MAPK1, MAPK3, MAPK6, MAPK7, MAPK9, MAPK10, MAPK11, MAPK12, MAPK14, NFKB1, NFKBIA, NFKBIB, NFKBIZ, MTOR, IL10RB, IL12RB2, IL18BP, TAFAIP6, TNFAIP8L1, TNFAIP8L3, CSF2RBP1, PDGFB, PDGFC, and CXCL9 (P < 0.05) were significantly increased in iMCD-TAFRO/NOS. Particularly, upregulated IL33 expression was demonstrated for the first time in iMCD-TAFRO/NOS. Thus, inflammatory signaling, such as JAK-STAT and MAPK, may be enhanced in iMCD-TAFRO/NOS and may be a cytokine storm.

Hyperpolarized (HP) magnetic resonance imaging (MRI) is a groundbreaking imaging platform advancing from research to clinical practice, offering new possibilities for real-time, non-invasive metabolic imaging. This review explores the latest advancements, challenges, and future directions of HP MRI, emphasizing its transformative impact on both translational research and clinical applications. By employing techniques such as dissolution Dynamic Nuclear Polarization (dDNP), Parahydrogen-Induced Polarization (PHIP), Signal Amplification by Reversible Exchange (SABRE), and Spin-Exchange Optical Pumping (SEOP), HP MRI achieves enhanced nuclear spin polarization, enabling in vivo visualization of metabolic pathways with exceptional sensitivity. Current challenges, such as limited imaging windows, complex pre-scan protocols, and data processing difficulties, are addressed through innovative solutions like advanced pulse sequences, bolus tracking, and kinetic modeling. We highlight the evolution of HP MRI technology, focusing on its potential to revolutionize disease diagnosis and monitoring by revealing metabolic processes beyond the reach of conventional MRI and positron emission tomography (PET). Key advancements include the development of novel tracers like [2-13C]pyruvate and [1-13C]-alpha-ketoglutarate and improved data analysis techniques, broadening the scope of clinical metabolic imaging. Future prospects emphasize integrating artificial intelligence, standardizing imaging protocols, and developing new hyperpolarized agents to enhance reproducibility and expand clinical capabilities particularly in oncology, cardiology, and neurology. Ultimately, we envisioned HP MRI as a standardized modality for dynamic metabolic imaging in clinical practice., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Rationale: Caustic substance ingestion is an emergency and life-threatening condition as it leads to tissue damage, acidosis, and multiorgan failure. This study presents a case report of hydrochloric acid ingestion and notably dark-red urine output due to acute tubular necrosis., Patient Concerns: A 59-year-old male presented with attempted suicide by ingesting 500 mL of hydrochloric acid (37%), and complained of severe abdominal pain and shortness of breath. Upon arrival, his vital signs showed a temperature of 34.3°C, blood pressure of 104/77 mm Hg, a pulse rate of 135 beats per minute, and the Glasgow Coma Scale E4V2M6. Following Foley catheter insertion, dark, bloody urine resulting from acute tubular necrosis was observed. His creatinine level was 1.1 mg/dL, and urinalysis showed 38 red blood cells per high-power field. Arterial blood gas analysis revealed metabolic acidosis., Diagnoses: The patient's condition rapidly deteriorated in the emergency room, revealing diffuse circumferential ulceration with necrosis in the esophagus (Zargar score grade 3b). An exploratory laparotomy was performed for acidosis with intractable shock, revealing up to 1500 mL of bloody ascites, and ischemic changes with loss of peristalsis throughout the small bowel to the cecum., Interventions: Esophagostomy with T-tube insertion was performed. Notably, stomach necrosis with perforation was identified, prompting a surgical consultation for primary perforation closure., Outcomes: During the operation, the patient experienced hemodynamic instability. The family confirmed the "Do Not Resuscitate" status, and he died in a critical state., Lessons: For corrosive injuries, early endoscopy was crucial in assessing the extent of the damage and guiding treatment in this patient. It is essential to perform an early endoscopic examination in cases of acute nephrotoxic tubular necrosis following hydrochloric acid ingestion. Surgical intervention is warranted if necrosis is detected in the corrosive tissue., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Kidney transplant is the treatment of choice for patients with end-stage renal disease. Early detection of allograft injury is important to delay or prevent irreversible damage., Purpose: To investigate the feasibility of hyperpolarized (HP) [1- 13 C]pyruvate MRI for assessing kidney allograft metabolism., Study Type: Prospective., Subjects: 6 participants (mean age, 45.2 ± 12.4 years, 2 females) scheduled for kidney allograft biopsy and 5 patients (mean age, 59.6 ± 10.4 years, 2 females) with renal cell carcinoma (RCC)., Field Strength/sequence: 3 Tesla, T2-weighted fast spin echo, multi-echo gradient echo, single shot diffusion-weighted echo-planar imaging, and time-resolved HP 13 C metabolite-selective imaging., Assessment: Five of the six kidney allograft participants underwent biopsy after MRI. Estimated glomerular filtration rate (eGFR) and urine protein-to-creatine ratio (uPCR) were collected within 4 weeks of MRI. Kidney metabolism was quantified from HP [1- 13 C]pyruvate MRI using the lactate-to-pyruvate ratio in allograft kidneys and non-tumor bearing kidneys from RCC patients., Statistical Tests: Descriptive statistics (mean ± standard deviation)., Results: Biopsy was performed a mean of 9 days (range 5-19 days) after HP [1- 13 C]pyruvate MRI. Three biopsies were normal, one showed low-grade fibrosis and one showed moderate microvascular inflammation. All had stable functioning allografts with eGFR > 60 mL/min/1.73 m 2 and normal uPCR. One participant who did not undergo biopsy had reduced eGFR of 49 mL/min/1.73 m 2 and elevated uPCR. The mean lactate-to-pyruvate ratio was 0.373 in participants with normal findings (n = 3) and 0.552 in participants with abnormal findings (n = 2). The lactate-to-pyruvate ratio was highest (0.847) in the participant with reduced eGFR and elevated uPRC. Native non-tumor bearing kidneys had a mean lactate-to-pyruvate ratio of 0.309., Data Conclusion: Stable allografts with normal findings at biopsy showed lactate-to-pyruvate ratios similar to native non-tumor bearing kidneys, whereas allografts with abnormal findings showed higher lactate-to-pyruvate ratios.

Narcissists are characterized by confidence, fragility, a desire for social approval without showing interest in others, charm, self-assurance, arrogance, and aggression. This study assesses the psychometric properties of the Arabic version of the Narcissistic Admiration and Rivalry Questionnaire (NARQ) among Algerian students ( N  = 714). Confirmatory factor and Rasch analyses were used. The NARQ consists of 18 items addressing six narcissism subscales under two main dimensions: rivalry and admiration. The results showed good saturation of the items on the six subscales and the three sub-scales on each of the two main dimensions, revealing a modest but positive correlation between rivalry and admiration. Moreover, the results of the Rasch model demonstrated that the scale aligns with the data, confirming the validity of the scale. This study offers valuable perspectives on assessing narcissism among Arabic populations and enhances our comprehension of the traits linked to narcissistic personalities., Competing Interests: The authors declare there are no competing interests., (©2024 Sabah et al.)

The successful integration of engineered gene circuits into host cells remains a significant challenge in synthetic biology due to circuit-host interactions, such as growth feedback, where the circuit influences cell growth and vice versa. Understanding the dynamics of circuit failures and identifying topologies resilient to growth feedback are crucial for both fundamental and applied research. Utilizing transcriptional regulation circuits with adaptation as a paradigm, we systematically study more than four hundred topological structures and uncover various categories of failures. Three dynamical mechanisms of circuit failures are identified: continuous deformation of the response curve, strengthened or induced oscillations, and sudden switching to coexisting attractors. Our extensive computations also uncover a scaling law between a circuit robustness measure and the strength of growth feedback. Despite the negative effects of growth feedback on the majority of circuit topologies, we identify several circuits that maintain optimal performance as designed, a feature important for applications.

Live vaccines are ideal for inducing immunity but suffer from the need to attenuate their pathogenicity or replication to preclude the possibility of escape. Unnatural amino acids (UAAs) provide a strategy to engineer stringent auxotrophies, yielding conditionally replication incompetent live bacteria with excellent safety profiles. Here, we engineer Pseudomonas aeruginosa to maintain auxotrophy for the UAA p-benzoyl-L-phenylalanine (BzF) through its incorporation into the essential protein DnaN. In vivo evolution using an Escherichia coli-based two-hybrid selection system enabled engineering of a mutant DnaN homodimeric interface completely dependent on a BzF-specific interaction. This engineered strain, Pa Vaccine, exhibits undetectable escape frequency (<10 -11 ) and shows excellent safety in naïve mice. Animals vaccinated via intranasal or intraperitoneal routes are protected from lethal challenge with pathogenic P. aeruginosa PA14. These results establish UAA-auxotrophic bacteria as promising candidates for bacterial vaccine therapy and outline a platform for expanding this technology to diverse bacterial pathogens., (© 2024. The Author(s).)

Background: Pulmonary hypertension (PH) represents an important phenotype in heart failure with preserved ejection fraction (HFpEF). However, management of PH-HFpEF is challenging because mechanisms involved in the regulation of PH-HFpEF remain unclear., Methods: We used a mass spectrometry-based comparative plasma proteomics approach as a sensitive and comprehensive hypothesis-generating discovery technique to profile proteins in patients with PH-HFpEF and control subjects. We then validated and investigated the role of one of the identified proteins using in vitro cell cultures, in vivo animal models, and independent cohort of human samples., Results: Plasma proteomics identified high protein abundance levels of B2M (β2-microglobulin) in patients with PH-HFpEF. Interestingly, both circulating and skeletal muscle levels of B2M were increased in mice with skeletal muscle SIRT3 (sirtuin-3) deficiency or high-fat diet-induced PH-HFpEF. Plasma and muscle biopsies from a validation cohort of PH-HFpEF patients were found to have increased B2M levels, which positively correlated with disease severity, especially pulmonary capillary wedge pressure and right atrial pressure at rest. Not only did the administration of exogenous B2M promote migration/proliferation in pulmonary arterial vascular endothelial cells but it also increased PCNA (proliferating cell nuclear antigen) expression and cell proliferation in pulmonary arterial vascular smooth muscle cells. Finally, B2m deletion improved glucose intolerance, reduced pulmonary vascular remodeling, lowered PH, and attenuated RV hypertrophy in mice with high-fat diet-induced PH-HFpEF., Conclusions: Patients with PH-HFpEF display higher circulating and skeletal muscle expression levels of B2M, the magnitude of which correlates with disease severity. Our findings also reveal a previously unknown pathogenic role of B2M in the regulation of pulmonary vascular proliferative remodeling and PH-HFpEF. These data suggest that circulating and skeletal muscle B2M can be promising targets for the management of PH-HFpEF., Competing Interests: Disclosures None.

Background: Teratomas are a common type of germ cell tumor. However, only a few reports on their genomic constitution have been published. The study of teratomas may provide a better understanding of their stepwise differentiation processes and molecular bases, which could prove useful for the development of tissue-engineering technologies., Methods: In the present study, we analyzed the copy number aberrations of nine ovarian mature cystic teratomas using array comparative genomic hybridization in an attempt to reveal their genomic aberrations., Results: The many chromosomal aberrations observed on array comparative genomic hybridization analysis reveal the complex genetics of this tumor. Amplifications and deletions of large DNA fragments were observed in some samples, while amplifications of EVX2 and HOXD9-HOXD13 on 2q31.1, NDUFV1 on 11q13.2, and RPL10, SNORA70, DNASE1L1, TAZ, ATP6AP1, and GDI1 on Xq28 were found in all nine mature cystic teratomas., Conclusions: Our results indicated that amplifications of these genes may play an important etiological role in teratoma formation. Moreover, amplifications of EVX2 and HOXD9-HOXD13 on 2q31.1, found on array comparative genomic hybridization, may help to explain the characteristics of teratomas in chondrogenesis and osteogenesis., (© 2024. The Author(s).)

Background In a population, when a disease is causing a symptom, the overall symptom incidence can be determined by proportions diseased, baseline symptom incidence, and risk ratios of developing the symptom due to the disease. There are various measures of association, including risk ratios. How risk ratios are linked to other measures of association, such as correlation coefficients and chi-squared statistics, has not been explicitly discussed. This study aims to demonstrate their connection via equations and simulations, assuming one disease causes symptoms. Methods The equations for correlation coefficients and chi-square statistics were rewritten using epidemiological measures: proportions diseased, baseline symptom incidence, and risk ratios. Simulations were conducted to test the accuracy of the equations. The baseline symptom incidence and the proportions diseased were assumed to be 0.05, 0.1, 0.2, 0.4, or 0.8. The risk ratios were assumed to be 0.5, 1, 2, 5, 10, and 25. Another disease that correlates with this disease was created (correlation = 0, 0.3, or 0.7). For each combination of symptom incidence, proportions diseased, risk ratios, and between-disease correlations, 10,000 subjects were simulated. The correlation coefficients and chi-squared statistics were approximated with epidemiologic measures and their interaction terms. R-squared was used to assess the importance of the epidemiologic measures. Results In the simulations, the overall symptom incidence, correlation coefficients, and chi-squared statistics between the disease and symptoms could be fully explained by the epidemiologic measures in the equations (R-squared = 1). When approximating correlation coefficients and chi-squared statistics with individual measures or their interaction terms, the importance of these measures depended on whether the at-risk incidence reached 1 or not. The numbers in the four cells in the contingency table predicted correlation coefficients, or chi-squared statistics, with different R-squared. Conclusion To our knowledge, this is the first study to translate the three epidemiologic measures (risk ratios, baseline symptom incidence, and proportions diseased) into correlation coefficients and chi-squared statistics. However, chi-squared statistics also depend on sample sizes. This study also provides a platform for developing teaching cases for students to investigate the causal relationship between diseases and symptoms or exposure and outcomes., Competing Interests: Human subjects: All authors have confirmed that this study did not involve human participants or tissue. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: Yi-Sheng Chao is employed by the Canadian Agency for Drugs and Technologies in Health. The other authors declared no conflicts of interest. Yi-Sheng Chao conducted this study as an independent researcher out of academic curiosity without any material support. No external funding was received for this study. This study is not associated with any patents, products in development, or marketed products., (Copyright © 2024, Chao et al.)

The literature on the nutritional needs and outcomes of critically ill children is scarce, especially on those with critical neurological illnesses (CNIs). Current evidence shows a lower mortality in patients who achieve two-thirds of their nutritional needs during the first week of pediatric intensive care unit (PICU) admission. We hypothesized that achieving 60% of the recommended dietary intake during the first week of a PICU stay is not feasible in patients with CNI. We designed an observational retrospective cohort study where we included all index admissions to the PICU in our institution of children (1 month to 18 years) with CNI from January 2018 to June 2021. We collected patient demographics, anthropometric measures, and caloric and protein intake (enteral and parenteral) information during the first week of PICU admission. Goal adequacy for calories and protein was defined as [(intake/recommended) × 100] ≥ 60%. A total of 1112 patients were included in the nutrition assessment, 12% of whom were underweight (weight for age z score < -2). Of this group, 180 met the criteria for nutrition support evaluation. On the third day of admission, 50% of the patients < 2 years achieved caloric and protein goal adequacy, compared to 25% of patients > 2 years, with p -values of 0.0003 and 0.0004, respectively. Among the underweight patients, 60% achieved both caloric and protein goal adequacy by day 3 vs. 30% of non-underweight patients with p -values of 0.0006 and 0.002, respectively. The results show that achieving 60% of the recommended dietary intake by days 5 and 7 of admission was feasible in more than half of the patients in this cohort. Additionally, children who were evaluated by a clinical dietician during the first 48 h of PICU admission reached higher nutrition adequacy.

Traditional neural network models of associative memories were used to store and retrieve static patterns. We develop reservoir-computing based memories for complex dynamical attractors, under two common recalling scenarios in neuropsychology: location-addressable with an index channel and content-addressable without such a channel. We demonstrate that, for location-addressable retrieval, a single reservoir computing machine can memorize a large number of periodic and chaotic attractors, each retrievable with a specific index value. We articulate control strategies to achieve successful switching among the attractors, unveil the mechanism behind failed switching, and uncover various scaling behaviors between the number of stored attractors and the reservoir network size. For content-addressable retrieval, we exploit multistability with cue signals, where the stored attractors coexist in the high-dimensional phase space of the reservoir network. As the length of the cue signal increases through a critical value, a high success rate can be achieved. The work provides foundational insights into developing long-term memories and itinerancy for complex dynamical patterns., (© 2024. The Author(s).)

This study uses Monte Carlo simulation and experimental measurements to develop a predictive model for estimating the external dose rate associated with permanent radioactive source implantation in prostate cancer patients. The objective is to estimate the accuracy of the patient's external dose rate measurement. First, I-125 radioactive sources were implanted into Mylar window water phantoms to simulate the permanent implantation of these sources in patients. Water phantom experimental measurement was combined with Monte Carlo simulation to develop predictive equations, whose performance was verified against external clinical data. The model's accuracy in predicting the external dose rate in patients with permanently implanted I-125 radioactive sources was high (R 2 = 0.999). A comparative analysis of the experimental measurements and the Monte Carlo simulations revealed that the maximum discrepancy between the measured and calculated values for the water phantom was less than 5.00%. The model is practical for radiation safety assessments, enabling the evaluation of radiation exposure risks to individuals around patients with permanently implanted I-125 radioactive sources.

Background: The effect of elevated preoperative liver enzyme levels on postoperative outcomes is a topic of concern to clinicians. This study explored the association between elevated preoperative liver enzyme levels and surgical outcomes in patients undergoing orthopedic surgery., Methods: Using the American College of Surgeons National Surgical Quality Improvement Program database, we obtained data on adult patients who received nonemergency orthopedic surgery under general anesthesia between 2011 and 2021., Results: We evaluated the data of 477,524 patients, of whom 6.1% (24 197 patients) had elevated preoperative serum glutamic oxaloacetic transaminase (SGOT) levels. An elevated SGOT level was significantly associated with 30-day postoperative mortality (adjusted hazard ratio, 1.62; 95% confidence interval, 1.39 to 1.90). We determined that the mortality rate rose with SGOT levels. The results remained unchanged after propensity score matching., Conclusion: Elevated preoperative SGOT levels constitute an independent risk factor for 30-day postoperative mortality and are proportionately associated with the risk of 30-day postoperative mortality., (© 2024. The Author(s).)

Hyperpolarized (HP) carbon-13 ( 13 C) MRI represents an innovative approach for noninvasive, real-time assessment of dynamic metabolic flux, with potential integration into routine clinical MRI. The use of [1- 13 C]pyruvate as a probe and its conversion to [1- 13 C]lactate constitute an extensively explored metabolic pathway. This review comprehensively outlines the establishment of HP 13 C-MRI, covering multidisciplinary team collaboration, hardware prerequisites, probe preparation, hyperpolarization techniques, imaging acquisition, and data analysis. This article discusses the clinical applications of HP 13 C-MRI across various anatomical domains, including the brain, heart, skeletal muscle, breast, liver, kidney, pancreas, and prostate. Each section highlights the specific applications and findings pertinent to these regions, emphasizing the potential versatility of HP 13 C-MRI in diverse clinical contexts. This review serves as a comprehensive update, bridging technical aspects with clinical applications and offering insights into the ongoing advancements in HP 13 C-MRI., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2024 The Korean Society of Radiology.)

Background: High levels of neutrophil extracellular trap (NET) formation or NETosis and autoantibodies are related to poor prognosis and disease severity of COVID-19 patients. Human angiotensin-converting enzyme 2 (ACE2) cross-reactive anti-severe acute respiratory syndrome coronavirus 2 spike protein receptor-binding domain (SARS-CoV-2 RBD) antibodies (CR Abs) have been reported as one of the sources of anti-ACE2 autoantibodies. However, the pathological implications of CR Abs in NET formation remain unknown., Methods: In this study, we first assessed the presence of CR Abs in the sera of COVID-19 patients with different severity by serological analysis. Sera and purified IgG from CR Abs positive COVID-19 patients as well as a mouse monoclonal Ab (mAb 127) that can recognize both ACE2 and the RBD were tested for their influence on NETosis and the possible mechanisms involved were studied., Results: An association between CR Abs levels and the severity of COVID-19 in 120 patients was found. The CR Abs-positive sera and IgG from severe COVID-19 patients and mAb 127 significantly activated human leukocytes and triggered NETosis, in the presence of RBD. This NETosis, triggered by the coexistence of CR Abs and RBD, activated thrombus-related cells but was abolished when the interaction between CR Abs and ACE2 or Fc receptors was disrupted. We also revealed that CR Abs-induced NETosis was suppressed in the presence of recombinant ACE2 or the Src family kinase inhibitor, dasatinib. Furthermore, we found that COVID-19 vaccination not only reduced COVID-19 severity but also prevented the production of CR Abs after SARS-CoV-2 infection., Conclusions: Our findings provide possible pathogenic effects of CR Abs in exacerbating COVID-19 by enhancing NETosis, highlighting ACE2 and dasatinib as potential treatments, and supporting the benefit of vaccination in reducing disease severity and CR Abs production in COVID-19 patients., (© 2024. The Author(s).)

Background: Monitoring pyruvate metabolism in the spleen is important for assessing immune activity and achieving successful radiotherapy for cervical cancer due to the significance of the abscopal effect. We aimed to explore the feasibility of utilizing hyperpolarized (HP) [1- 13 C]-pyruvate magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) to evaluate pyruvate metabolism in the human spleen, with the aim of identifying potential candidates for radiotherapy in cervical cancer., Methods: This prospective study recruited six female patients with cervical cancer (median age 55 years; range 39-60) evaluated using HP [1- 13 C]-pyruvate MRI/MRS at baseline and 2 weeks after radiotherapy. Proton ( 1 H) diffusion-weighted MRI was performed in parallel to estimate splenic cellularity. The primary outcome was defined as tumor response to radiotherapy. The Student t-test was used for comparing 13 C data between the groups., Results: The splenic HP [1- 13 C]-lactate-to-total carbon (tC) ratio was 5.6-fold lower in the responders than in the non-responders at baseline (p = 0.009). The splenic [1- 13 C]-lactate-to-tC ratio revealed a 1.7-fold increase (p = 0.415) and the splenic [1- 13 C]-alanine-to-tC ratio revealed a 1.8-fold increase after radiotherapy (p = 0.482). The blood leukocyte differential count revealed an increased proportion of neutrophils two weeks following treatment, indicating enhanced immune activity (p = 0.013). The splenic apparent diffusion coefficient values between the groups were not significantly different., Conclusions: This exploratory study revealed the feasibility of HP [1- 13 C]-pyruvate MRS of the spleen for evaluating baseline immune potential, which was associated with clinical outcomes of cervical cancer after radiotherapy., Trial Registration: ClinicalTrials.gov NCT04951921 , registered 7 July 2021., Relevance Statement: This prospective study revealed the feasibility of using HP 13 C MRI/MRS for assessing pyruvate metabolism of the spleen to evaluate the patients' immune potential that is associated with radiotherapeutic clinical outcomes in cervical cancer., Key Points: • Effective radiotherapy induces abscopal effect via altering immune metabolism. • Hyperpolarized 13 C MRS evaluates patients' immune potential non-invasively. • Pyruvate-to-lactate conversion in the spleen is elevated following radiotherapy., (© 2024. The Author(s).)

Shorebirds (order Charadriiformes) are among the world's most threatened avian taxa. Within the East Asian-Australasian Flyway (EAAF), a major threat to shorebirds' survival may be the gauntlet of pollution along the flyway. Metals, persistent organic pollutants (POPs), and per-/polyfluoroalkyl substances (PFASs) persist in the environment to the detriment of wildlife. In this study, we analysed element and PFAS concentrations in blood from 142 individuals across six species of Arctic-breeding migratory shorebirds with contrasting population trends, to discern species- and site-specific pollution differences, and determine how pollution correlated with population trends of EAAF shorebirds. Potential within-year pollution variations were investigated by blood-sampling birds at two sites, representing different points in the birds' annual migrations: staging in Taiwan on southward migrations and at non-breeding grounds in Western Australia (WA). Species' pollutant concentrations were compared to established population trends. Concentrations of potentially toxic elements were low in most individuals regardless of species. PFASs (range: <0.001-141 ng/g), Hg (<0.001-9910 ng/g) and Pb (<0.01-1210 ng/g) were higher in Taiwan than in WA (PFAS Taiwan median: 14.5 ng/g, WA median: 3.45 ng/g; Hg Taiwan: 338 ng/g, WA: 23.4 ng/g; Pb Taiwan: 36.8 ng/g, WA: 2.26 ng/g). Meanwhile As (range <0.001-8840 ng/g) and Se (290-47600 ng/g) were higher in WA than Taiwan (As Taiwan median: 500 ng/g, WA median: 1660 ng/g; Se Taiwan: 5490 ng/g, Se WA: 23700 ng/g). Nevertheless, pollutant concentrations in a subset of individuals may exceed sublethal effect thresholds (As, Se and PFASs). Finally, we found no consistent differences in pollution among species and demonstrated no correlation between pollution and population trends, suggesting pollution is likely not a major driver for population declines of EAAF shorebirds. However, ongoing and locally heavy environmental degradation and exposure to other contaminants not investigated here, such as POPs, warrants continued consideration when managing EAAF shorebird populations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

We aimed to evaluate the association between systemic sclerosis (SSc) and major cerebrovascular/cardiovascular risks through a systematic approach. Databases were systematically searched from their inception to October 10, 2023 for studies comparing cerebrovascular/cardiovascular event rates between patients with SSc and controls. The primary outcome was the stroke risk in patients with SSc. Secondary outcomes included risk of myocardial infarction (MI), cardiovascular disease (CVD), peripheral vascular disease (PVD), and venous thromboembolism (VTE). Seventeen studies with 6,642,297 participants were included. SSc was associated with a significantly increased risk of stroke (HR, 1.64; 95% confidence interval [CI], 1.35-2.01), CVD (HR, 2.12; 95% CI, 1.36-3.3), MI (HR, 2.15; 95% CI, 1.23-3.77), VTE (HR, 2.75; 95% CI, 1.77-4.28), and PVD (HR, 5.23; 95% CI, 4.25-6.45). Subgroup analysis revealed a significantly increased stroke risk in the non-Asian group (HR, 1.55; 95% CI, 1.26-1.9), while the Asian group displayed a higher but not statistically significant risk (HR, 1.86; 95% CI, 0.97-3.55). The study found that SSc is associated with a significantly increased risk of cerebrovascular/cardiovascular events. These findings highlight the importance of vasculopathy in SSc and suggest the need for enhanced clinical monitoring and preventive measures in this high-risk population., (© 2024. The Author(s).)

The ability to detect single photons has led to the advancement of numerous research fields 1-11 . Although various types of single-photon detector have been developed 12 , because of two main factors-that is, (1) the need for operating at cryogenic temperature 13,14 and (2) the incompatibility with complementary metal-oxide-semiconductor (CMOS) fabrication processes 15,16 -so far, to our knowledge, only Si-based single-photon avalanche diode (SPAD) 17,18 has gained mainstream success and has been used in consumer electronics. With the growing demand to shift the operation wavelength from near-infrared to short-wavelength infrared (SWIR) for better safety and performance 19-21 , an alternative solution is required because Si has negligible optical absorption for wavelengths beyond 1 µm. Here we report a CMOS-compatible, high-performing germanium-silicon SPAD operated at room temperature, featuring a noise-equivalent power improvement over the previous Ge-based SPADs 22-28 by 2-3.5 orders of magnitude. Key parameters such as dark count rate, single-photon detection probability at 1,310 nm, timing jitter, after-pulsing characteristic time and after-pulsing probability are, respectively, measured as 19 kHz µm -2 , 12%, 188 ps, ~90 ns and <1%, with a low breakdown voltage of 10.26 V and a small excess bias of 0.75 V. Three-dimensional point-cloud images are captured with direct time-of-flight technique as proof of concept. This work paves the way towards using single-photon-sensitive SWIR sensors, imagers and photonic integrated circuits in everyday life., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Postoperative ileus (POI) is a complication that may occur after abdominal or nonabdominal surgery. Intravenous dexmedetomidine (Dex) has been reported to accelerate postoperative gastrointestinal function recovery; however, updated evidence is required to confirm its robustness., Methods: To identify randomized controlled trials examining the effects of perioperative intravenous Dex on gastrointestinal function recovery in patients undergoing noncardiac surgery, databases including MEDLINE, EMBASE, Google Scholar, and Cochrane Library were searched on August 2023. The primary outcome was time to first flatus. Secondary outcomes included time to oral intake and defecation as well as postoperative pain scores, postoperative nausea/vomiting (PONV), risk of hemodynamic instability, and length of hospital stay (LOS). To confirm its robustness, subgroup analyses and trial sequential analysis were performed., Results: The meta-analysis of 22 randomized controlled trials with 2566 patients showed that Dex significantly reduced the time to flatus [mean difference (MD):-7.19 h, P <0.00001), time to oral intake (MD: -6.44 h, P =0.001), time to defecation (MD:-13.84 h, P =0.008), LOS (MD:-1.08 days, P <0.0001), and PONV risk (risk ratio: 0.61, P <0.00001) without differences in hemodynamic stability and pain severity compared with the control group. Trial sequential analysis supported sufficient evidence favoring Dex for accelerating bowel function. Subgroup analyses confirmed the positive impact of Dex on the time to flatus across different surgical categories and sexes. However, this benefit has not been observed in studies conducted in regions outside China., Conclusions: Perioperative intravenous Dex may enhance postoperative gastrointestinal function recovery and reduce LOS, thereby validating its use in patients for whom postoperative ileus is a significant concern., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

One of the very fundamental attributes for telencephalic neural computation in mammals involves network activities oscillating beyond the initial trigger. The continuing and automated processing of transient inputs shall constitute the basis of cognition and intelligence but may lead to neuropsychiatric disorders such as epileptic seizures if carried so far as to engross part of or the whole telencephalic system. From a conventional view of the basic design of the telencephalic local circuitry, the GABAergic interneurons (INs) and glutamatergic pyramidal neurons (PNs) make negative feedback loops which would regulate the neural activities back to the original state. The drive for the most intriguing self-perpetuating telencephalic activities, then, has not been posed and characterized. We found activity-dependent deployment and delineated functional consequences of the electrical synapses directly linking INs and PNs in the amygdala, a prototypical telencephalic circuitry. These electrical synapses endow INs dual (a faster excitatory and a slower inhibitory) actions on PNs, providing a network-intrinsic excitatory drive that fuels the IN-PN interconnected circuitries and enables persistent oscillations with preservation of GABAergic negative feedback. Moreover, the entities of electrical synapses between INs and PNs are engaged in and disengaged from functioning in a highly dynamic way according to neural activities, which then determine the spatiotemporal scale of recruited oscillating networks. This study uncovers a special wide-range and context-dependent plasticity for wiring/rewiring of brain networks. Epileptogenesis or a wide spectrum of clinical disorders may ensue, however, from different scales of pathological extension of this unique form of telencephalic plasticity., Competing Interests: Competing interests statement:The authors declare no competing interest.

Large-area metamorphic stretchable sensor networks are desirable in haptic sensing and next-generation electronics. Triboelectric nanogenerator-based self-powered tactile sensors in single-electrode mode constitute one of the best solutions with ideal attributes. However, their large-area multiplexing utilizations are restricted by severe misrecognition between sensing nodes and high-density internal circuits. Here, we provide an electrical signal shielding strategy delivering a large-area multiplexing self-powered untethered triboelectric electronic skin (UTE-skin) with an ultralow misrecognition rate (0.20%). An omnidirectionally stretchable carbon black-Ecoflex composite-based shielding layer is developed to effectively attenuate electrostatic interference from wirings, guaranteeing low-level noise in sensing matrices. UTE-skin operates reliably under 100% uniaxial, 100% biaxial, and 400% isotropic strains, achieving high-quality pressure imaging and multi-touch real-time visualization. Smart gloves for tactile recognition, intelligent insoles for gait analysis, and deformable human-machine interfaces are demonstrated. This work signifies a substantial breakthrough in haptic sensing, offering solutions for the previously challenging issue of large-area multiplexing sensing arrays., (© 2024. The Author(s).)

Background: Diabetes self-management education (DSME) improves glycemic and metabolic control. However, the frequency, duration and sustainability of DSME for improving metabolic control have not been well studied., Methods: The Diabetes Share Care Program (DSCP) stage 1 provided DSME every 3 months. If participants entering DSCP stage 1 ≥ 2 years and HbA1c < 7%, they can be transferred to stage 2 (DSME frequency: once a year). Three-to-one matching between DSCP stage 1 and stage 2 groups based on the propensity score method to match the two groups in terms of HbA1c and diabetes duration. We identified 311 people living with type 2 diabetes in DSCP stage 1 and 86 in stage 2 and evaluated their metabolic control and healthy behaviors annually for 5 years., Results: In the first year, HbA1c in the DSCP stage 2 group was significantly lower than that in the stage 1 group. In the first and the fifth years, the percentage of patients achieving HbA1c < 7% was significantly higher in the DSCP stage 2 group than the stage 1 group. There was no significant difference in other metabolic parameters between the two groups during the 5-year follow-up. Self-monitoring of blood glucose (SMBG) frequency was associated with a reduced HbA1c after 5 years (95% CI: -0.0665 to -0.0004)., Conclusion: We demonstrated sustainable effects of at least 2-year DSME on achieving better glycemic control for at least 1 year. SMBG contributed to improved glycemic control. The results may be applied to the reimbursement strategy in diabetes education., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest relevant to this study., (Copyright © 2023 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Background: Immune checkpoint inhibitors (ICI) are promising treatment options for various cancers. However, their use is associated with immune-related adverse events (irAEs), including ICI-induced diabetes mellitus (ICI-DM). This study aimed to investigate the clinical features of ICI-DM, with a particular focus on alterations to pancreatic volume., Methods: We conducted a retrospective review of 2829 patients who received ICI treatment at the Chang Gung Memorial Hospital, Linkou, between January 2014 and December 2021. New-onset diabetes or diabetic ketoacidosis (DKA) was identified in ten patients receiving ICI therapy. Pancreatic volumes were assessed by manual segmentation of computed tomography (CT) images before and after ICI-DM diagnosis., Results: Among these ten patients, nivolumab was the most commonly used ICI (50.0%), followed by pembrolizumab (30.0%) and atezolizumab (20.0%). One patient received combination therapy with nivolumab and ipilimumab. The median age was 63.01 years (range: 40.1 - 87.8). ICI-DM developed after a median of 13.5 cycles (range: 2 - 42) of ICI treatment or 9.85 months (range:1.5 - 21.3) since ICI initiation. The initial presentation was DKA in 60.0% of patients. All patients had low or undetectable C-peptide levels (range: <0.033 - 0.133 nmol/L) and were negative for most type 1 diabetes mellitus (T1DM)-related autoantibodies; only one patient tested positive for glutamic acid decarboxylase antibodies. CT imaging revealed significant pancreatic atrophy, with a median pancreatic volume decrease of 19.92% (P = 0.038) from baseline and sustained significant decline at last follow-up (median - 37.14%, P = 0.012)., Conclusions: ICI-DM is often accompanied by pancreatic atrophy and approximately two-thirds of patients initially present with DKA. Although the majority of ICI-DM patients lack T1DM-related autoantibodies, identifying diminished pancreatic volumes through CT imaging provides valuable clues into the subclinical aspects of ICI-DM development, aiding in the prevention of diabetic emergencies., Trial Registration: Not applicable., (© 2024. The Author(s).)

Objectives This study aims to understand the statistical significance of the associations between diagnoses and symptoms based on simulations that have been used to understand the interpretability of mental illness diagnoses. Methods The symptoms for the diagnosis of major depressive episodes, dysthymic disorder, and manic episodes were extracted from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR, American Psychiatric Association, Philadelphia, Pennsylvania). Without real-world symptom data, we simulated populations using various combinations of symptom prevalence and correlations. Assuming symptoms occurred with similar prevalence and correlations, for each combination of symptom prevalence (0.05, 0.1, 0.3, 0.5, and 0.7) and correlation (0, 0.1, 0.4, 0.7, and 0.9), 100 cohorts with 10,000 individuals were randomly created. Diagnoses were made according to the DSM-IV-TR criteria. The associations between the diagnoses and their input symptoms were quantified with odds ratios and correlation coefficients. P-values from 100 cohorts for each combination of symptom prevalence and correlation were summarized. Results Three mental illness diagnoses were not significantly correlated with their own symptoms in all simulations, particularly when symptoms were not correlated, except for the symptom in the major criteria of major depressive episodes or dysthymic disorder. The symptoms for the diagnosis of major depressive episodes and dysthymic disorder were significantly correlated with these two diagnoses in some simulations, assuming 0.1, 0.4, 0.7, or 0.9 symptom correlations, except for one symptom. The overlap in the input symptoms for the diagnosis of major depressive episodes and dysthymic disorder also leads to significant correlations between these two diagnoses, assuming 0.1, 0.4, 0.7, and 0.9 correlations between input symptoms. Manic episodes are not significantly associated with the input symptoms of major depressive episodes and dysthymic disorder. Conclusion There are challenges to establish the causation between psychiatric symptoms and mental illness diagnoses. There is insufficient prevalence and incidence data to show all psychiatric symptoms exist or can be observed in patients. The diagnostic accuracy of symptoms to detect a disease cause is far from perfect. Assuming the symptoms of three mood disorders may present in patients, three diagnoses are not significantly associated with all psychiatric symptoms used to diagnose them. The diagnostic criteria of the three diagnoses have not been designed to guarantee significant associations between symptoms and diagnoses. Because statistical associations are important for making causal inferences, there may be a lack of causation between diagnoses and symptoms. Previous research has identified factors that lead to insignificant associations between diagnoses and symptoms, including biases due to data processing and a lack of epidemiological evidence to support the design of mental illness diagnostic criteria., Competing Interests: YSC is employed by the Canadian Agency for Drugs and Technologies in Health. YSC conducted this study as an independent researcher out of academic curiosity without any material support. The other authors declared no competing interests. No external funding was received for this study. This study is not associated with any patents, products in development or marketed products., (Copyright © 2024, Chao et al.)

A rotator cuff tear is a prevalent ailment affecting the shoulder joint. The clinical efficacy of combined therapy remains uncertain for partial rotator cuff tears. In this study, we integrated extracorporeal shockwave therapy (ESWT) with platelet-rich plasma (PRP) injection, juxtaposed with PRP in isolation. Both cohorts exhibited significant improvements in visual analogue scale (VAS), Constant-Murley score (CMS), degrees of forward flexion, abduction, internal rotation, and external rotation, and the sum of range of motion (SROM) over the six-month assessment period. The application of ESWT in conjunction with PRP exhibited notable additional enhancements in both forward flexion ( p = 0.033) and abduction ( p = 0.015) after one month. Furthermore, a substantial augmentation in the range of shoulder motion (SROM) ( p < 0.001) was observed after six months. We employed isobaric tag for relative and absolute quantitation (iTRAQ) to analyze the differential plasma protein expression in serum samples procured from the two groups after one month. The concentrations of S100A8 ( p = 0.042) and S100A9 ( p = 0.034), known to modulate local inflammation, were both lower in the ESWT + PRP cohort. These findings not only underscore the advantages of combined therapy but also illuminate the associated molecular changes.